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A series of new fluorescent symmetric dimeric bisbenzimidazoles DBP ( n ) bearing bisbenzimidazole fragments joined by oligomethylene linkers with a central 1,4-piperazine residue were synthesized. The complex formation of DBP ( n ) in the DNA minor groove was demonstrated. The DBP ( n ) at micromolar concentrations inhibit in vitro eukaryotic DNA topoisomerase I and prokaryotic DNA methyltransferase (MTase) M.SssI. The DBP ( n ) were soluble well in aqueous solutions and could penetrate cell and nuclear membranes and stain DNA in live cells. The DBP ( n ) displayed a moderate effect on the reactivation of gene expression. [ABSTRACT FROM AUTHOR]

In this study, a monomeric ( MB ) and a dimeric ( DB ) bisbenzimidazoles were identified as novel proteasome inhibitors of the trypsin-like activity located on β2c sites of the constitutive 20S proteasome (IC 50 values at 2–4 μM range). Remarkably, they were further shown to be 100- and 200-fold more potent inhibitors of the immunoproteasome trypsin-like activity (β2i sites, IC 50 = 24 nM) than of the homologous constitutive activity. Molecular models of inhibitor/enzyme complexes in the two types of trypsin-like sites and corresponding computed binding energy values corroborated kinetic data. Different binding modes were suggested for MB and DB to the β2c and β2i trypsic sites. Each pointed to better contacts of the ligand inside the β2i active site than for β2c site. MB and DB represent the first selective inhibitors of the immunoproteasome trypsin-like activity described to date and can be considered as prototypes for inhibiting this activity. [ABSTRACT FROM AUTHOR]